AB0019 AUTOANTIBODY BIOMARKERS OF IMMUNE-RELATED ADVERSE EVENTS AND SURVIVAL IN MELANOMA PATIENTS RECEIVING IMMUNE CHECKPOINT INHIBITOR THERAPY
Authors: C. Aude, N. Ghosh, D. Jannat-Khah, K. K. Chan, M. Postow, H. Larman, A. Bass
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Immune checkpoint inhibitor (ICI) therapy has greatly improved the prognosis of advanced cancers but is often complicated by immune-related adverse events (irAEs). Biomarkers of ICI safety and efficacy are needed. <h3>Objectives</h3> To identify autoantibodies (AAbs) associated with irAEs and cancer outcomes in ICI-treated patients. <h3>Methods</h3> This analysis used clinical data and biospecimens from a prospective trial of 60 patients with advanced melanoma who received 2-4 doses of combination ICI (anti-PD1 + anti-CTLA4) followed by anti-PD1 monotherapy. <sup>[1]</sup> Patients were followed for three years for irAE development, cancer progression, and death. Plasma was collected at baseline and six weeks after ICI initiation and assayed for AAbs using PhIP-Seq with a human peptide library spanning the entire human proteome. Baseline levels of AAbs with a ≥2 fold-change in ≥10 patients at follow-up (n = 833 AAbs) were concurrently included in a bootstrapped LASSO Cox proportional hazards model (1000 replications; α = 0.5; λ chosen by cross-validation for each replication) that was separately run for each outcome: ≥1 severe irAE (CTCAE grade ≥ 3), progression-free survival (PFS), and overall survival (OS). The proportion of times each AAb was replicated was reported as its "validation frequency."<sup>[2]</sup> Hazard ratio confidence intervals were reported after individually calculating bias-corrected and accelerated (BCa) bootstrap intervals (1000 replications) for each AAb. The AAbs with the highest validation frequencies were used for Partial Least Squares Discriminant Analysis (PLS-DA) clustering. <h3>Results</h3> Among the 60 patients, 47% developed a severe irAE, 25% progressed, and 23% died. <b>Table 1</b> shows the six AAbs with the highest validation frequencies for severe irAE, PFS, and OS. PLS-DA was able to cluster patients by the development of severe irAEs using only six AAbs with a 10-fold cross-validated AUROC of 0.86 ± 0.01 (p &lt;.001) (<b>Figure 1</b>). PLS-DA performed similarly well for PFS and OS. <b>Table 1</b> reflects that higher levels of the identified AAbs at baseline were associated with worse PFS and OS (HR &gt; 1); this pattern remained true across the 25 AAbs with the highest validation frequencies for PFS (21/25, 84%) and OS (23/25, 92%). Conversely, amongst the top AAbs linked to severe irAEs, lower levels in the majority (15/25, 60%) of the identified AAbs were associated with this outcome (HR &lt; 1). Most of the identified top AAbs were unique to each outcome, but there was some overlap: PFS and OS shared seven AAbs (28%), PFS and severe irAEs shared two AAbs (8%), and OS and severe irAEs shared one AAb (4%). No AAbs overlapped between more than two outcomes. <h3>Conclusion</h3> These results suggest that specific autoantibodies may be useful biomarkers for predicting outcomes in melanoma patients receiving ICI therapy. However, these results require validation. <h3>References</h3> [1]Postow MA, et al. Journal of Clinical Oncology 2022;40:1059-1067 [2]Yang JJ, et al. Blood 2012;120:4197-4204 <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Carlos Aude: None declared, Nilasha Ghosh Grant/research support from: Hospital for Special Surgery, Deanna Jannat-Khah Shareholder of: Walgreens Boots Alliance, AstraZeneca, and Cytodyn, Grant/research support from: Hospital for Special Surgery, Karmela Kim Chan: None declared, Michael Postow Consultant of: BMS, Merck, Novartis, Eisai, Pfizer, and Chugai, Grant/research support from: RGenix, Infinity, BMS, Merck, and Novartis, H Larman Consultant of: Scientific Advisory Board member for TScan Therapeutics, Employee of: Founder of ImmuneID, Portal Bioscience, and Alchemab, Anne Bass Grant/research support from: Hospital for Special Surgery, Memorial Sloan Kettering Cancer Center, and the Rheumatology Research Foundation.